Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated protein C (APC) serves as an 'on demand' anticoagulant. Defects in the APC anticoagulant pathway are underlying risk factors for the development of venous and arterial thrombosis. APC has recently been shown to significantly reduce mortality in patients with severe sepsis, presumably by virtue of its ability to down-regulate coagulation as well as inflammation. Our objective was to develop an assay that, for the first time, permits rapid detection of plasma APC. This assay will expedite studies of APC in a variety of vascular disease states including sepsis, severe atherosclerosis, diabetes, and vasculitis. By generating a highly APC-specific monoclonal antibody (HAPC 1555), we have developed an assay that, for the first time, allows rapid detection of plasma APC. The Kd measured for the interaction between APC and HAPC 1555 based on BIAcore studies and binding to immobilized HAPC on microtiter plates is 6.2 +/- 0.9 and 8.8 +/- 1.0 nmol L(-1), respectively. The interaction between HAPC 1555 and APC is Ca2+-dependent, with a Ca2+ concentration of 313 +/- 48 micro mol L(-1) required for half maximal binding. HAPC 1555 interferes with APC-mediated inactivation of factor (F)Va in the presence and absence of phospholipids, suggesting that HAPC 1555 binds to the FVa binding domain of APC. When HAPC 1555 was used in an APC enzyme capture assay, therapeutic APC levels could be measured in 1.5 h, and physiologic levels of APC could be detected between 3 and 19 h. APC levels were also shown to vary markedly in patients with severe sepsis. The rapidity of our APC assay makes APC detection in patients practical clinically. This assay will expedite studies of APC in a variety of vascular disease states including sepsis, severe atherosclerosis, diabetes, and vasculitis.
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PMID:A monoclonal antibody against activated protein C allows rapid detection of activated protein C in plasma and reveals a calcium ion dependent epitope involved in factor Va inactivation. 1499 20

We investigated the impact of GH administration on endothelial adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, in vivo and in vitro. Soluble VCAM-1, E-selectin, and C-reactive protein concentrations were measured before and after treatment in 25 healthy subjects and 25 adult GH-deficient (GHD) patients randomized to GH treatment or placebo. Furthermore, we studied the direct effect of GH and IGF-I and serum from GH-treated subjects on basal and TNF alpha-stimulated expression of VCAM-1 and E-selectin on cultured human umbilical vein endothelial cells. Baseline levels of VCAM-1, but not E-selectin, were significantly lower in GHD patients than in healthy subjects (362 +/- 15 microg/liter vs. 516 +/- 21 microg/liter, P < 0.001) and increased in GHD patients during GH treatment, compared with placebo [net difference between groups 151.8 microg/liter (95% confidence interval: 95.0-208.7 microg/liter); P < 0.0001]. In human umbilical vein endothelial cells, there was no direct stimulatory effect of either GH or IGF-I on the expression of VCAM-1 and E-selectin, but serum from GH-treated healthy subjects significantly increased the expression of VCAM-1 (P < 0.01). Our findings are compatible with the notion that GH may stimulate the expression of VCAM-1 indirectly through modulation of circulating factors. VCAM-1-mediated leukocyte extravasation is implicated in several illnesses including atherosclerosis and multiple-organ failure in sepsis, and we hypothesize that enhanced expression of VCAM-1 may contribute to the detrimental effects of GH in critically ill patients.
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PMID:Growth hormone increases vascular cell adhesion molecule 1 expression: in vivo and in vitro evidence. 1476 13

Besides cyclooxygenase and NO-synthase, another distinct endothelial pathway, endothelium-dependent hyperpolarization (EDHF), is involved in the relaxation of the vascular smooth muscle cells. EDHF has been demonstrated unequivocally in various blood vessels from different species, including human, and is likely to play an important role in cardiovascular physiology. This alternative pathway involves the activation of two populations of endothelial potassium channels, the small conductance and intermediate conductance calcium-activated potassium channels (SK(Ca) and IK(Ca), respectively). EDHF-mediated responses are clearly altered in various pathological conditions (ageing, hypertension, atherosclerosis, hypercholesterolemia, heart failure, ischemia-reperfusion, angioplasty, eclampsia, diabetes, sepsis). Therapeutic or adjutant interventions (angiotensin converting enzyme inhibitors, antagonist of the angiotensin receptor, estrogen, omega-3 polyunsaturated fatty acids, polyphenol derivatives, potassium and/or calcium intake) can restore these responses, suggesting that the improvement of the EDHF pathway contributes to the observed beneficial effect of these various substances. However, the improvement or restoration of EDHF responses has not been, yet, the direct purpose of any pharmaceutical effort. Activating endothelial IK(Ca) and/or SK(Ca) or increasing their expression as well as improving myo-endothelial communication, for instance by increasing the expression of connexin(s), could become interesting therapeutic targets.
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PMID:EDHF: new therapeutic targets? 1502 34

Cardiovascular infections due to Salmonella enterica are infrequently reported, so their clinical features, prognosis, and optimal treatment are not completely known. Mortality associated with aortitis and endocarditis caused by nontyphoidal Salmonella remains exceedingly high. In this review of cases of cardiovascular infections due to Salmonella enterica studied in 2 hospitals in Madrid, we tried to assess the clinical manifestations and the procedures leading to diagnosis in addition to treatment and outcome. To complete the spectrum of infections related to cardiovascular surgery, cases of postoperative mediastinitis, pericarditis, and infections associated with cardiac devices were also included.Twenty-three patients were reviewed: 11 had mycotic aneurysms; 7 had endocarditis; 2 had device-related infections; and 3 had pericarditis, mediastinitis, and infection of an arteriovenous fistula, respectively. The risk of endovascular infection in patients older than 60 years with bacteremia due to nontyphoidal Salmonella was 23%. Most patients with aortitis had risk factors for atherosclerosis, and 6 had preexisting atherosclerotic aortic aneurysms. All except 1 patient with endocarditis had underlying cardiac disorders. Acquired immunodeficiency disease (AIDS) was a major risk factor for salmonella bacteremia in 1 patient with aortitis and 1 with endocarditis. Fever, unremitting sepsis, "breakthrough" and relapsing bacteremia were the most common clinical findings. In addition, abdominal or thoracic pain and cardiac failure and pericarditis were common features in patients with aortitis and endocarditis respectively. Computed tomography (CT) scan, arteriography, and echocardiography were the main diagnostic tools. Mortality associated with mycotic aneurysms and endocarditis due to S. enterica was 45% and 28%, respectively. Thoracic aneurysms, rupture, and shock at the time of diagnosis were associated with increased mortality in patients with aortitis. In situ bypass grafting was successfully performed in most cases. After surgery, antimicrobial therapy was continued for 4-9 weeks. No relapses were observed after a mean follow-up of 64 months. Antimicrobial therapy alone or combined with valve replacement or excision of a ventricular aneurysm was successful treatment for most patients with salmonella endocarditis. Combined medical and surgical treatment was required for patients with mediastinitis and pericarditis, and patients with device-related infections needed removal of the complete device. Diagnosis of aortitis due to nontyphoidal Salmonella should be established as early as possible to reduce mortality. Patients older than 60 years who have positive blood cultures for Salmonella along with fever and back, abdominal, or chest pain should have an extensive workup for infective aortitis. Immediate bactericidal antimicrobial therapy should be started and a CT scan should be performed on an emergency basis. If a mycotic aneurysm is found, surgical resection should follow as soon as possible. Resection of the aneurysm with in situ bypass grafting is the procedure of choice. Postoperative antimicrobial therapy for 6-8 weeks seems enough to avoid relapses. Optimal treatment of patients with endocarditis occurring on ventricular aneurysms must include resection of the aneurysmal sac. Salmonella endocarditis can be successfully treated with antimicrobials alone. Valve replacement should be reserved for patients with cardiac failure or persisting sepsis, and for those who relapse after discontinuation of antimicrobial therapy.
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PMID:The spectrum of cardiovascular infections due to Salmonella enterica: a review of clinical features and factors determining outcome. 1502 66

A new fluorogenic substrate for the specific detection of organophosphatase (OPase) activity has been designed and evaluated. Our results indicate that 7-diethylphospho-6,8-difluor-4-methylumbelliferyl (DEPFMU) is hydrolyzed specifically by the OPases, mammalian serum paraoxonase and bacterial organophosphorus hydrolase (OPH). The apparent K(m) of DEPFMU is 29 microM for OPH and 91 and 200 microM for the PON1 L(55)R(192) and PON1 L(55)Q(192) isoforms of human paraoxonase, respectively. DEPFMU-based assay systems are 10-100 times more sensitive for OPH and mammalian paraoxonase detection than existing methods. Importantly, DEPFMU is poorly hydrolyzed by both serum and cellular phosphatases and, therefore, may be used as part of a robust and sensitive assay for detecting not only purified, but also highly impure, preparations of OPase such as blood samples. The superior sensitivity of DEPFMU makes it potentially useful in the search for new enzymes that may hydrolyze nerve poisons such as sarin, soman, and VX, monitoring the decontamination of organophosphates (OPs) by OPH and determining serum paraoxonase activity which appears to be important for protection against atherosclerosis, sepsis, and OP toxicity.
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PMID:A fluorogenic substrate for detection of organophosphatase activity. 1503 22

MD-2 is an accessory protein of the Toll-like receptor (TLR)-4, necessary for assembling a receptor complex to sense low quantities of lipopolysaccharide in order to subsequently trigger innate immune responses. MD-2 and TLR-4 are expressed on a variety of immunocompetent cells. Mutations within the TLR-4 gene have been shown to attenuate immune responses against lipopolysaccharide in mice. In humans, a TLR-4 polymorphism has been associated with a higher risk for developing severe Gram-negative sepsis and with a lower risk for atherosclerosis. Since MD-2 is an essential part of the lipopolysaccharide receptor complex, we screened 20 patients that underwent surgical cancer therapy for novel MD-2 mutations by a single-strand conformation polymorphism technique. In one patient we found an A --> G substitution at position 103, resulting in an amino-acid exchange from Thr 35 to Ala. Reporter gene assays revealed that this mutation resulted in a reduced lipopolysaccharide-induced signaling. The patient displayed an uneventful postoperative course, with the exception of slightly decreased TNF-alpha levels after in vitro stimulation with LPS as compared to wt patients. Genotyping of a further 41 patients by a newly developed Lightcycler/FRET method failed to detect any additional polymorphism carriers, indicating that this is a rare mutation.
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PMID:A coding mutation within the first exon of the human MD-2 gene results in decreased lipopolysaccharide-induced signaling. 1505 66

The classical 'cascade/waterfall' hypothesis formulated to explain in vitro coagulation organised the amplification processes into the intrinsic and extrinsic pathways. Recent molecular biology and clinical data indicate that tissue factor/factor-VII interaction is the primary cellular initiator of coagulation in vivo. The process of blood coagulation is divided into an initiation phase followed by a propagation phase. The discovery of tissue factor pathway inhibitor further supports the revised theory of coagulation. Tissue factor is also a signalling receptor. Recent evidence has shown that blood-borne tissue factor has an important procoagulant function in sepsis, atherosclerosis and cancer, and other functions beyond haemostasis such as immune function and metastases.
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PMID:Tissue factor and tissue factor pathway inhibitor. 1509 42

Tissue factor (TF) is best known as the primary cellular initiator of blood coagulation. After vessel injury, the TF:FVIIa complex activates the coagulation protease cascade, which leads to fibrin deposition and activation of platelets. TF deficiency causes embryonic lethality in the mouse and there have been no reports of TF deficiency in humans. These results indicate that TF is essential for life, most likely because of its central role in hemostasis. In addition, aberrant TF expression within the vasculature initiates life-threatening thrombosis in various diseases, such as sepsis, atherosclerosis, and cancer. Finally, recent studies have revealed a nonhemostatic role of TF in the generation of coagulation proteases and subsequent activation of protease activated receptors (PARs) on vascular cells. This TF-dependent signaling contributes to a variety of biological processes, including inflammation, angiogenesis, metastasis, and cell migration. This review focuses on the roles of TF in hemostasis, thrombosis, and vascular development.
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PMID:Role of tissue factor in hemostasis, thrombosis, and vascular development. 1511 36

Fifteen years after its discovery, NO has fully reached an established position in physiology, medicine and therapeutics. It is difficult to find a biological function or a pathological condition where NO does not play a relevant role. Discoveries in the NO field have historically evolved from cardiovascular research, although its influences have already covered nearly all the medical specialties. This review analyzes, step by step, the pathway through which NO is synthesized in the cells of the cardiovascular system and the main physiological and pathological routes it undergoes once it is released. We focus on various diseases affecting the cardiovascular system (atherosclerosis, hypertension, diabetes mellitus and septic shock). We describe in detail those steps of the NO pathway in which anomalies have been detected and may account for the pathophysiology of these diseases. In atherosclerosis, hypertension and diabetes mellitus, the endothelial form of NOS is upregulated, but is very sensitive to environmental conditions, such as substrate or cofactor deficiencies or increases in LDL or glucose. In this situation NOS synthesizes superoxide anion instead of NO leading to oxidative and nitrosative stress. In diabetes mellitus and, very importantly, in septic shock, the inducible form of NOS is highly upregulated. Overproduction of NO appears to underlie the hypotension and tissue damage of septicemia and the destruction of beta-cells in diabetes mellitus. New knowledge of the role of NO in these diseases has started to influence therapeutic design. We also review the current status of research on NO-based therapies.
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PMID:Cardiovascular diseases and the nitric oxide pathway. 1532 Apr 80

The transmembrane glycoprotein tissue factor (TF) is the initiator of the coagulation cascade in vivo. When TF is exposed to blood, it forms a high-affinity complex with the coagulation factors factor VII/activated factor VIIa (FVII/VIIa), activating factor IX and factor X, and ultimately leading to the formation of an insoluble fibrin clot. TF plays an essential role in hemostasis by restraining hemorrhage after vessel wall injury. An overview of biological and physiological aspects of TF, covering aspects consequential for thrombosis and hemostasis such as TF cell biology and biochemistry, blood-borne (circulating) TF, TF associated with microparticles, TF encryption-decryption, and regulation of TF activity and expression is presented. However, the emerging role of TF in the pathogenesis of diseases such as sepsis, atherosclerosis, certain cancers and diseases characterized by pathological fibrin deposition such as disseminated intravascular coagulation and thrombosis, has directed attention to the development of novel inhibitors of tissue factor for use as antithrombotic drugs. The main advantage of inhibitors of the TF*FVIIa pathway is that such inhibitors have the potential of inhibiting the coagulation cascade at its earliest stage. Thus, such therapeutics exert minimal disturbance of systemic hemostasis since they act locally at the site of vascular injury.
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PMID:Tissue factor: (patho)physiology and cellular biology. 1538 18


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